«40% of US adults have CKM syndrome»

Dr. Terence McManus: Actually I think it was a response to new treatments, and how the build-up of clinical trial data helps us understand the commonality between the causes of these diseases. CKM is a syndrome with underlying symptoms, implying a shared underlying pathophysiology. By creating the term CKM, the AHA has underscored the connection between obesity, type-2 diabetes, chronic kidney disease (CKD) and the cardiovascular (CV) diseases. Starting in early age, the progression of CKM is determined by a combination of genetic as well as social factors such as an unhealthy lifestyle. Approximately 40% of the adult population in the US has CKM, so there is a very large patient population and commercial opportunity should treatments be developed which can target the root cause, or more likely, causes.

The GLP-1 agonists and SGLT-2 inhibitors could be seen as the first drug classes which address several drivers of early CKM, both of which originally starting in diabetes. The SELECT study in obesity conducted by Novo Nordisk with GLP-1 agonist Wegovy showed a reduced risk of CV disease by 20%. The FLOW study found that patients taking Wegovy reduced the risk of CKD progression as well as CV and kidney death by 24%. The SGLT2 inhibitors such as Farxiga have moved beyond diabetes treatment and into heart failure and CKD treatment. While less in the headlines than the GLP-1s because they do not induce weight-loss, the SGLT2 inhibitors could form a backbone with other CKM drugs. Indeed, AstraZeneca is doing a lot of work on such oral combination therapies, for example zibotentan/Farxiga.

Along with treating obesity, which is very important, LDL cholesterol control remains an issue. While the statin class of drugs, for example Lipitor, have been available in cheap generic forms for many years, millions of patients either cannot tolerate the side effects or are not compliant with treatment. Actually, 16 million US patients taking statins are still not at LDL target! This therefore represents a high-unmet need and large potential market opportunity. We see Novartis as well placed with its 6-monthly PCSK-9 siRNA injection Leqvio. In the pipeline, we would also point to AstraZeneca‘s oral PCSK9 called AZD0780, which is in mid-stage development.

There is a lot being investigated, but within the CV part of this syndrome, we would point to lipoprotein(a). Novartis and Ionis pharmaceuticals are testing the hypothesis that lowering lipoprotein(a) or Lp(a) when it is elevated, will result in reduced CV events with a drug called pelacarsen. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for CV disease. An estimated 20% of the world’s population have elevated Lp(a) levels. As it has not been shown so far that lowering Lp(a) is beneficial, the pivotal clinical trial in 2025 will be an important catalyst for Novartis. Amgen are also targeting Lp(a) in clinical trials, but are a few years behind. Unlike high LDL cholesterol, Lp(a) is not related to lifestyle or exercise, therefore should the link with CV events be proven, the need for pharmacological treatment will be clear.

Sure, fatty liver is something seen as a consequence of CKM. Again, the GLP-1 agonists are being investigated here, along with several other mechanisms. In addition, the first clinical trials are underway to investigate the effects of CKM on the development of neurodegenerative diseases like Alzheimer‘s disease decades before their progression.